In developed nations, the prognosis for people living with HIV has improved with the advent of anti-retroviral therapy (ART). However, ART is neither able to cure infection nor to fully restore health due, in part, to ongoing HIV replication in tisses sanctuaries. Studies in both the SIV-infected rhesus macaque and in HIV-infected humans have implicated lymphoid tissue - lymph nodes in particular - as important sites of ongoing replication. The factors governing bio-distribution of drugs are complex and multifactorial and we perceive the effective delivery of free (non-encapsulated) drug to all sites of potential HIV replication to represent a formidable challenge. The delivery of nanoparticle (NP) encapsulated drugs is an alternative, but here the efficient clearance of NP drug carriers by the reticuloendothelial system can be expected to interfere with delivery. We propose in this R01 study to adapt a technology that we have previously developed to covalently attach NPs to T-cells, thus converting them into living carriers of ARV drug cargo that we term T-Pharmacytes (TPH). A unique aspect of our approach is that NPs remain at the cell surface for weeks, and do not interfere with T-cell trafficking or effector functions. In our first Aim we will conjugate NPs to bulk CD4+ or CD8+ T-cells and take advantage of the natural homing of these cells to the lymphoid tissues to deliver ARVs to these HIV sanctuary sites in the NOD/SCID BLT mouse model. In a potentially very powerful approach, our second Aim will be to directly link NPs to well-characterized HIV-specific CTL clones that have been isolated from HIV- infected subjects, and test these in a huCD4+ NSG mouse model. In this latter approach, we will load NPs with both ARVs and an IL-15 superagonist (IL-15SA). The latter will both support the in vivo survival of adoptively transferred cells, and will act as a latency-reversing drug (LRD). We envision a chain of events whereby: (1) HIV-specific TPH will traffic into HIV sanctuary sites (2) TPH will encounter cognate antigen resulting in the lysis of productively infected cells and the local accumulation of TPH (3) IL-15SA and ARVs delivery will be concentrated at these sites resulting in i) induction of HIV expression from local latently-infected cells and ii) suppression of any new rounds of infection (4) HIV-specific TPH (enhanced in function and survival by IL-15SA) will recognize and eliminate exposed latently-infected cells. Our third Aim seeks to build upon preliminary studies to directly conjugate bulk or HIV-specific T-cells to NPs in vivo thus negating the need for ex vivo manipulations of cells. This approach will be developed and tested by a multidisciplinary team bringing expertise in nanotechnology/cell therapy, HIV T-cell immunology, and humanized mouse models of HIV infection. Ultimately our results will provide insights into the relative importance of lymphoid tissue viral reservoirs to overall persistence and may lead to therapeutic approaches comprising either the ongoing suppression of, or the eradication of, HIV reservoirs from ARV-treated individuals.